Non-typhoidal Salmonella enterica subspecies I, serovar typhimurium is a growing and evolving threat, both in Sub-Saharan Africa, where it is now a leading cause of invasive, bacteremic infections, and also in the United States, where it has been responsible for numerous food-related outbreaks, where it has expanded its contamination profile historically into poultry, and recently has apparently been able to colonize (or at least survive robustly) on peanuts and tomatoes. In both cases, it appears likely that selection pressures are driving evolution of S. typhimurium to acquire and/or lose biological capabilities to take advantage of new routes of transmission. Less is known about what elements in the genome of S. typhimurium have been altered to enable these adaptations, or what impact that may have on the human immune response. We will use high-throughput in-vitro phenotyping to characterize strains causing diarrheal vs. non-diarrheal disease from Sub-Saharan Africa. To better understand the genetic traits behind adaptation in S. typhimurium we will use next-generation whole genome to fully characterize all allelic differences in core genome elements, and to inventory missing genes, and define the presence of novel genes in many strains from NTS in Africa, and from varying foodborne sources in the USA. Correlated genetic elements will be functionally verified by allelic replacement and in some cases demonstrated by animal model virulence tests. For functionally verified genetic markers, simplified assays will be developed (PCR, Allele-specific PCR or locus-specific DNA sequencing), which can then be implemented in the field to assess their prevalence and clinical significance.